Field of the Invention
The present invention relates to methods and designs for reducing the pressure required to pass liquid through a membrane for the first time, particularly in relation to use in sample processing for medical diagnostic applications. More generally, the invention discusses how a liquid exposed to or experiencing capillary forces or capillary pressure can be ‘reset’ from one set of governing conditions which may be characterized by requiring a high pressure to overcome, to a new set of governing conditions which may be characterized by requiring much less pressure to overcome, or to induce a continuation a flow through a system.
Description of Related Art
Many filtration systems experience a transient spike of liquid flow pressure as liquid is passing through the filtration system for the first time. However, once liquid has passed through the filtration membrane, a steady state pressure is reached which can be significantly lower than the pressure spike. In large, industrial filtration systems, this transient pressure spike is usually of little concern, because the whole system is designed to withstand this spike. However, in low cost, handheld, disposable systems, managing this pressure requirement can be very difficult, expensive, or impossible.
This pressure spike is caused by the capillarity of the filtration membrane itself. If the membrane material is hydrophobic, aqueous liquid will not want to enter the membrane and the increased pressure is required to force the liquid in. If the membrane material is hydrophilic, aqueous liquid will not want to leave the membrane, but is tightly held within the pore structure of the membrane, and the pressure transient is needed to push the liquid through, or out, of the membrane (breakthrough pressure). However, once liquid is flowing through the membrane, the capillarity of the membrane ceases to exist, and flow is governed by a different set of conditions that does not include the hydrophilicity or hydrophobicity of the membrane material, but rather its pore size, percent porosity, liquid viscosity, flow rates, and any relevant downstream flow conditions. This is the steady state condition.
This disclosure will discuss hydrophilic systems, or systems where the membrane is comprised of a hydrophilic material, or where the membrane or critical surfaces of the membrane can be rendered hydrophilic.
The term Capillarity refers to capillary forces that exist at a liquid/gas interface, or liquid/air interface, where surface tension, or interface tension exists between the liquid and the air. Capillarity is dependent on the dimensions of the system, such as the pore size of the membrane, the type of liquid, e.g. aqueous or organic, salt content, etc., and the surface properties of the flow channel, such as hydrophobic or hydrophilic including the degree of hydrophobicity or hydrophilicity (contact angle). Once liquid is already pushed through a membrane, the liquid/air interface is no longer present in the membrane, which is why the capillary forces or capillarity ceases to exist within the membrane.
In contrast to pressure transients experienced by membrane filtration systems, another system, referred to as a lateral flow system, exists where no pressure transient takes place and, in fact, no externally applied pressure is required to pass liquid through a membrane. In a lateral flow system, capillary forces completely control the flow of liquid through the system. Different membranes, including filtration membranes, are layered one on top of each other, and liquid passes from one membrane to the next due to the increased capillarity of each successive membrane. A filtration membrane that is often used in such systems is the PALL Vivid™ Plasma Separation Membrane that is capable of separating plasma from whole blood. Normally such filtration, due to the small pore size, would require substantial pressure to force the plasma or serum to exit the membrane. Such high pressure often causes hemolysis, or breaking of red blood cells in the whole blood, which reduces the quality of the filtrate. Instead, according to operational instructions of the membrane itself, all that is required to extract the plasma through the membrane is to place the membrane on another membrane of higher capillarity, then flow proceeds automatically.
However, what if it is desired to remove the plasma from the membrane, or from a successive membrane? This is difficult to do using existing technologies, prior to the technology discussed in this disclosure. Instead, if it is desired to separate plasma from whole blood in a non-filtration membrane system, a centrifuge is usually used.
Many new medical diagnostic systems use microfluidic technologies to control liquid flow, process liquid samples, and analyze their content. Microfluidics involves the processing and movement of liquid through small channels, such as channels between 0.1 to 1000 μm in diameter. Liquid flow is controlled by capillary forces, positive pressure pumps, suction, or electric forces. These include the processing and analysis of whole blood. In some of these systems attempts are made to separate plasma from whole blood. However, whenever the microfluidic flow channels become very small, such as less than 1 to 5 μm in diameter, such as what may be needed to separate plasma from whole blood, the system quickly becomes impractical to commercialize due to the very expensive manufacturing methods that are required to produce products reliably with such small dimensions, or due to the extremely low flow rates that are generated, or very high pumping pressures that may be required if the system is driven by positive pressure, or because of the difficulty in sealing such a system due to high pressures or high probability of blocking small flow channels during the sealing process, or other related complication.
The use of a membrane to separate plasma from whole blood has several advantages over the use of microchannels or a network of microchannels for separation. These advantages include the fact that membranes for this purpose are already commercially available in large quantities, are relatively inexpensive, robust, durable, and easy to use. Also, their quality and manufacture can be controlled, tested and performed ‘off-line’ of the quality and control and manufacture of a complete diagnostic system. They do not represent a limiting factor in the production of a diagnostic device, which is in strong contrast to the use of microchannels as a means of size-exclusion based filtration.
It is highly desirable and beneficial for a system to be developed that has the advantages of membrane based filtration, but does not require the filtrate to be retained and processed within a downstream membrane system, and does not require the use of buffer, diluent, solvent, or pressure in order to cause the filtrate to be passed through the membrane and be available for collection. It is also desirable for this method of filtration, when used for medical diagnostics, to be able to interface directly with enclosed microfluidic-based diagnostics, or to be collectable and used in some macro diagnostic system, or even reintroduced to a membrane based systems after additional processing on the filtrate has taken place, such as metering or measuring the amount of filtrate that is present before it is passed downstream.